The Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions

Abstract

Cancer continues to be a significant global health issue, influenced by genetic mutations and external factors like carcinogenic exposure, lifestyle choices, and chronic inflammation. The myelocytomatosis (MYC) oncogene family, including c-MYC, MYCN, and MYCL, is essential in the development, progression, and metastasis of various cancers such as breast, colorectal, osteosarcoma, and neuroblastoma. Beyond its well-known roles in cell growth and metabolism, MYC significantly shapes the tumor immune microenvironment (TIME) by altering immune cell dynamics, antigen presentation, and checkpoint expression. It contributes to immune evasion by upregulating checkpoints such as programmed death-ligand 1 (PD-L1) and cluster of differentiation (CD)47, suppressing antigen-presenting major histocompatibility complex (MHC) molecules, and promoting the recruitment of suppressive immune cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). While direct targeting of MYC has proven challenging, recent advances in therapeutic strategies, including MYC-MYC-associated factor X (MAX) dimerization inhibitors, bromodomain and extra terminal domain (BET) and cyclin dependent kinase (CDK) inhibitors, synthetic lethality approaches, and epigenetic modulators, have shown promising results in preclinical and early clinical settings. This review discusses MYC’s comprehensive impact on TIME and examines the promising therapeutic strategies of MYC inhibition in enhancing the effectiveness of immunotherapies, supported by recent preclinical and clinical findings.